The Cause – Missense Mutation Achondroplasia (ACH) is caused by a missense mutation in FGFR3 (fibroblast growth factor receptor 3) on chromosome 4p in humans
This nucleotide, # 1138 in exon 10 on chromosome 4, has the highest mutation rate known
In 97% of patients, an adenine replaces the normal guanine at this position (observed in cDNA)
3% have a cytosine instead

Consequence Both mutations result in the production of the amino acid arginine instead of glycine
This production of arginine enhances gene function and # of FGFR3 signals released
Mitosis is promoted, but cell differentiation is depressed due to enhancement of gene function
Inhibits proliferation and terminal differentiation, resulting in reduced bone growth

Cause of Mutation Studies show correlation with paternal age
Appears that the vast majority of FGFR3 mutations arise as new mutations during spermatogenesis before Meiosis I
All mutations studied so far occur on the paternal chromosome

More Genetics ACH is an autosomal dominant trait, meaning that a diseased parent has a 50% chance of passing it on (pedigree next slide)
Despite these odds, almost 90% of patients have de novo, or spontaneous, ACH
Probably due to either of two missense muta-tions or difficulty of the diseased to reproduce

Phenotype & Symptoms Cont. Statistics show mortality rate more than doubles the general population
Does not effect intelligence
Biggest challenge is overcoming social ineptitude and low self-esteem
(Television show – “Little People, Big World” on TLC)
- Depression is common

Treatment New method of adding height, called distraction osteogenesis, is being researched
- Lengthen tibia bone with very few risks
- Increase of 4.0 +/- 1.98 centimeters
Growth hormone therapy is still under study
Gene Therapy possibility
Altered clothing, car-pedal extensions, respect from average-sized individuals, and even a support group (see next slide) all help the low self-esteem and depression that is common

Support Group Therapy Research shows 5,000 – 10,000 achondroplasts in the U.S.A. and 65,000 on Earth
Support groups allow for sharing of experiences and more social interaction
Little People of America, founded by actor Billy Barty, has more than 5,000 members
Help to lead a normal life…